Cleft Palate induced by Sulfur Mustard in mice fetus.

Sulfur Mustard (SM) is a chemical warfare agent which was widely used in the World War I and more recently during Gulf war in the early 1980s'. SM is a strong alkylating agent with known mutagenic and carcinogenic effects; but only few studies have been published on its teratogenicity. Since SM has been widely used as a chemical weapon by the Iraqi regime against the Iranian soldiers as well as the civilian population particularly pregnant women in the border area; therefore, the investigation of SM adverse effects on cleft malformations which is one of the most frequent congenital anomalies is considered in this study. An experimental work has been carried out in embryopathy in mouse with intraperitoneal injection of 0.75 and 1.5 mg/kg SM at different periods of gestation. Cleft lip and palate were examined by stereomicroscopy. Current data demonstrate that exposure with SM on the 11th day of gestation can increase the incidence of cleft defects in comparison with control group (P<0.001). These results also show that SM treatment in GD 11 and 13 can lead to more anomalies compared with GD 14 (P<0.001). They also show that the teratogenic effects of SM are restrictively under the influence of the threshold dose and time of gestation. The present results suggest that exposure to sufficient doses of SM on critical days of gestation may increase the risk of congenital cleft malformations.

The destructive effects of SM are well recognized. The eyes, the skin, and the respiratory tract are the principal organ targets of SM toxicity (4)(5)(6)(7)(8). SM is highly lipophilic and is absorbed very quickly through the skin. After a latent period of 6-24 h erythema and blisters appear on the skin (6).
Pulmonary complications mainly on the upper respiratory tract such as hemorrhagic inflammation, sore throat, hoarseness, cough, bronchitis, and bronchopneumonia are observed in SM-exposed victims (6,9). Additionally, lung cancers had been reported in fishermen who were exposed to SM and in workers of SM manufacturing plants (10)(11)(12).
Because of its alkylating and electrophilic properties, SM can alter chemical functional groups  (6,7,13,14). SM like other mustards agents such as nitrogen mustard may possess teratogenic effects (15).
Facial clefts represent the majority of these defects and can rise at any stage of development due to perturbation that alter the extracellular matrix as well as affect the patterning, migration, proliferation, and differentiation of cells (16 (17,22). In addition, clefts may vary according to several influencing factors including time (4,23-28) and race (4,(29)(30)(31). This report minimizes the time and race variability factors, thus focusing more precisely on environment and in particular SM-exposure.
In the event of an SM attack during war or a terrorist incident, the pregnant women might be one of the victims who survive the SM-exposure.
However, the transplacentally exposed fetus may bear long term consequences.
Since comparatively little work has been conducted to assess the impact of SM on fetus teratogenicity, investigation of SM developmental toxicity should be considered. The aim of this study was to define the teratogenic effects of SM on cleft lip/palate on mouse embryo.

Results
The results of pregnancy in SM treated groups are compared with control groups in 9 groups (Table 1). No indicative organ anomalies were observed in control negative and solution control groups. These results show that the incidence of cleft malformations in Phenytoin treated group was higher than control groups. In addition, the current data demonstrate that injection of 1.5 mg/kg in GD 11 significantly increase the incidence of cleft anomalies in comparison with the control group (p<0.001), but no obvious teratogenic activity of SM could be observed on GD14. The rate of anomalies was also slightly higher in GD11 compared with GD13. On the other hand, the incidence of malformations were more prominent in the 1.5 mg/kg than 0.75 mg/kg (p=0.01).

Discussion
Sulfur mustard (SM), commonly known as mustard gas, is an alkylating agent which was widely used as a chemical warfare during Gulf war Considering the destructive effects of mustard gas on different organs, the logical question that one may ask is why despite the conventional laws that prohibit the use of these weapons, nevertheless, it has been recently used against the innocent human beings.